Loneliness is a common experience among older individuals that can adversely affect physical and mental health. The effect of loneliness on health is mediated, at least in part, by psychological stress. Because loneliness is a subjective feeling that is independent of a person's social network, it is difficult to predict this state and anticipate its effect on an individual's future health. In order to develop more accurate predictors, the proposed work aims to identify the genetic (G) and environmental (E) factors that contribute to loneliness, and how their interaction (GxE) impacts performance on a laboratory test of psychological stress reactivity. The molecular mechanisms of these GxE interactions may involve changes in gene expression or epigenetic modifications. These mechanisms would presumably be localized within brain circuits mediating the stress response or associated behaviors. However, aside from data from my group, the sites of GxE interactions in the human brain are currently unknown. Moreover, because gene expression changes and epigenetic modifications are likely tissue-specific, and healthy human brain tissue from donors with known life stress histories is ordinarily unavailable to investigators, there are currently no data that can shed light on molecular mechanisms of GxE interactions in the human brain. Thus, the field is currently in critical need of an integrated approach to the study of GxE interactions on human behavior, its neural substrate, and its molecular mechanisms. The proposed work offers such an integrated approach by focusing on GxE effects on individuals' physiological response to an acute psychosocial stressor (Aim 1); identifying the neural circuits that reflect this GxE interaction (Aim 2); and analyzing gene expression profiles and epigenetic markers in these circuits, based on postmortem human brain tissue obtained from donors with known genotypes and stressful life events (Aim 3). The work is informed by the theoretical framework of the Neurotrophic Model, and focuses a priori on polymorphisms of three genes that are involved in stress reactivity: brain- derived neurotrophic factor (BDNF), the serotonin transporter gene (5-HTT), and the glucocorticoid receptor gene (NR3C1). PUBLIC HEALTH RELEVANCE: Aging is often accompanied by the loss of close social bonds and changes in life circumstances that cause loneliness and social stress, both of which can carry significant adverse health effects. The proposed work will investigate the genetic and environmental variables that contribute to individual differences in loneliness and social stress reactivity. This work is critical for identifying vulnerable individuals and developing tailored interventions.